US9993480B2ActiveUtilityA1

mTOR/JAK inhibitor combination therapy

80
Individually held — no corporate assignee on recordPriority: Feb 18, 2011Filed: Feb 17, 2012Granted: Jun 12, 2018
Est. expiryFeb 18, 2031(~4.6 yrs left)· nominal 20-yr term from priority
Inventors:Alessandro M. VannucchiCostanza BoganiPaola Guglielmelli
A61P 7/00A61P 43/00A61P 35/00A61P 35/02A61K 31/436A61K 31/519A61K 45/06A61K 2300/00A61K 31/506
80
PatentIndex Score
15
Cited by
307
References
23
Claims

Abstract

Provided herein is a combination therapy comprising an mTOR inhibitor and a JAK inhibitor. The combination therapy is useful for the treatment of a variety of cancers, including myeloproliferative neoplasms. The combination therapy is also useful for the treatment of any number of JAK-associated diseases.

Claims

exact text as granted — not AI-modified
The invention claimed is: 
     
       1. A method of treating a myeloproliferative neoplasm in a subject in need thereof, comprising administering to the subject synergistically effective amounts of an mTOR inhibitor and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, wherein the mTOR inhibitor is everolimus or 2-(4-Amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol. 
     
     
       2. The method of  claim 1 , wherein the mTOR inhibitor is everolimus. 
     
     
       3. The method of  claim 1 , wherein the mTOR inhibitor and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, are in a single formulation or unit dosage form. 
     
     
       4. The method of  claim 3 , further comprising a pharmaceutically acceptable carrier. 
     
     
       5. The method of  claim 1 , wherein the mTOR inhibitor and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, are administered separately. 
     
     
       6. The method of  claim 1 , wherein the myeloproliferative neoplasm is selected from the group consisting of chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), primary or idiopathic myelofibrosis (PMF), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, hypereosinophilic syndrome, systemic mastocytosis, and atypical chronic myelogenous leukemia. 
     
     
       7. The method of  claim 1 , wherein the myeloproliferative neoplasm is primary myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis. 
     
     
       8. The method of  claim 5 , wherein the subject is human. 
     
     
       9. The method of  claim 5 , wherein the treatment comprises administering the mTOR inhibitor and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, at substantially the same time. 
     
     
       10. The method of  claim 5 , wherein the treatment comprises administering the mTOR inhibitor and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, at different times. 
     
     
       11. The method of  claim 10 , wherein the mTOR inhibitor is administered to the subject, followed by administration of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof. 
     
     
       12. The method of  claim 10 , wherein (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, is administered to the subject, followed by administration of the mTOR inhibitor. 
     
     
       13. The method of  claim 5 , wherein the mTOR inhibitor and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, are in separate formulations or unit dosage forms. 
     
     
       14. The method of  claim 5 , wherein the mTOR inhibitor and/or (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, are administered at dosages that would not be effective when one or both of the mTOR inhibitor and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, are administered alone, but which amounts are effective in combination. 
     
     
       15. A method of inhibiting STAT5 phosphorylation, comprising administering synergistically effective amounts of an mTOR inhibitor and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, wherein the mTOR inhibitor is everolimus or 2-(4-Amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol. 
     
     
       16. The method of  claim 15 , wherein the mTOR inhibitor and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof are administered to a subject in need thereof. 
     
     
       17. The method of  claim 16 , wherein the administration of the mTOR inhibitor and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof treats a myeloproliferative neoplasm in the subject. 
     
     
       18. The method of  claim 17 , wherein the myeloproliferative neoplasm is selected from the group consisting of chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), primary or idiopathic myelofibrosis (PMF), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, hypereosinophilic syndrome, systemic mastocytosis, and atypical chronic myelogenous leukemia. 
     
     
       19. The method of  claim 17 , wherein the myeloproliferative neoplasm is primary myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis. 
     
     
       20. A composition comprising an mTOR inhibitor and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof in synergistically effective amounts, wherein the mTOR inhibitor is everolimus or 2-(4-Amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol. 
     
     
       21. The composition of  claim 20 , further comprising a pharmaceutically acceptable carrier. 
     
     
       22. A method of treating a myeloproliferative neoplasm in a subject in need thereof, comprising administering to the subject an effective amount of the composition of  claim 20 . 
     
     
       23. A method of treating a myeloproliferative neoplasm in a subject in need thereof, comprising administering to the subject synergistically effective amounts of an mTOR inhibitor and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, wherein the mTOR inhibitor is everolimus.

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